PROJECT SUMMARY Nonalcoholic steatohepatitis, or NASH, is a serious and escalating health threat in the United States, affecting at least 2-5% of the population, with a rising incidence paralleling the obesity epidemic. There are no effective medical treatments. NASH is a ?silent? liver disease characterized by hepatic accumulation of fat accompanied by inflammation and hepatocellular injury (?ballooning?). NASH is a progressive disease that can culminate in cirrhosis and a heightened risk of primary liver cancer. It is the second leading cause of liver failure and will supplant hepatitis C as the primary indication for liver transplantation by 2020. The accelerating impact of NASH underscores the urgent need to develop novel therapies that prevent progression or, in advanced stages, reverses inflammation, injury and fibrosis. Drug repurposing is an attractive approach to identify novel therapeutics for NASH because it can greatly shorten the drug development timeline. To exploit new computational strategies to uncover relevant repurposed drugs we applied a chemogenomic drug repurposing algorithm in collaboration with AstraZeneca, to identify novel indications for a set of AstraZeneca compounds that previously failed human efficacy studies for various indications apart from safety concerns. Our analysis identified a specific compound that previously failed efficacy trials for a gastrointestinal indication as a drug repurposing candidate for NASH. The compound's mechanism of action would be considered quite novel for treating NASH, and NASH would represent a leap to a completely new disease area compared to the compound's original indication. In the UH2 phase of this grant we propose to perform in vitro and in vivo pre- clinical studies to evaluate the efficacy of the repurposed compound for treating NASH. We will achieve this goal through the following aims: Aim 1) Experimentally validate molecular engagement of a novel drug repurposing candidate for NASH. Aim 2) Evaluate the efficacy of a novel drug repurposing candidate for NASH using a murine model of disease. If the milestones from the UH2 phase are successfully achieved and a ?go? decision point is reached, we will use the UH3 phase of the grant to plan a phase 2a clinical trial. We have assembled a multidisciplinary team with demonstrated expertise in liver disease, drug repurposing, genomics, basic and clinical analysis of liver disease, clinical trials, and pharmaceutic drug development. The team capabilities and expertise along with the established collaboration between Mount Sinai and AstraZeneca provide a seamless path to move from pre-clinical studies directly to human clinical trials.